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The present invention relates to the field of chemical synthesis, and in
particular to a method for synthesizing
1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-formamidine hydrochloride,
which is an important intermediate of Riociguat that is an
anti-thromboembolic-disease medicine. The method is characterized in
that: 3-iodo-1H-pyrazolo[3,4-b]pyridine is used as a raw material; the
raw material is reacted with fluorobenzyl bromide to form a compound
(10); the compound (10) is reacted with zinc cyanide to form a compound
(6); the compound (6) is reacted with sodium methoxide, ammonium
chloride, acetic acid and methanol to form a compound (8); and the
compound (8) is reacted with chlorine hydride gas to form
1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-formamidine hydrochloride.
The method has the characteristics of cheap and readily available raw
materials, high yield, mild reaction conditions and the like, and is a
synthesis method having a large-scale preparation value.

2. The preparation method according to claim 1, wherein the molar ratio of compound (9): o-fluorobenzyl bromide:potassium carbonate is 1:1.about.1.5:1.5.about.3.0.

3. The preparation method according to claim 1, wherein in step VII, the reaction solvent is tetrahydrofuran, N,N-dimethylformamide or dimethylsulfoxide.

4. The preparation method according to claim 1, wherein in step VIII, the reaction temperature is 100.about.150.degree. C. and the reaction solvent is N,N-dimethylacetamide.

5. The preparation method according to claim 1, wherein in step VIII, the molar ratio of compound (10) and zinc cyanide is 1:0.7.about.1:1.2.

6. The preparation method according to claim 1, wherein in step IX, the reaction solvent is methyl tertiary butyl ether.

Description

FIELD OF THE INVENTION

The present invention relates to the field of chemical synthesis, and particularly to a method for synthesizing 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride, which is an important intermediate of anti-thromboembolic
disease medicine Riociguat.

BACKGROUND OF THE INVENTION

Riociguat can be used to treat chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary hypertension, which has a structural formula as follows:

##STR00001##

Chem. Med. Chem. 2009, 4, 853-865 reports the following method:

##STR00002## ##STR00003##

1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride is an important intermediate for synthesis of Riociguat.

In respect to the preparation of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine (hereinafter referred to as "compound 8") hydrochloride (hereinafter referred to as "compound 11"), US20020173514 reports the following method:

This reported synthesis method has the following defects: raw material (1) and raw material (2) are hardly available in domestic market and are expensive; the yield in the first two steps is low; the postprocessing of (II) needs column
chromatography; mass production cannot be realized.

SUMMARY OF THE INVENTION

The present invention discloses a method for preparing 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride (compound 11). It mainly solves the technical problem that the conventional preparation of
1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride has a low yield and cannot realize mass production.

The innovative points of the preparation method provided in the present invention are: 3-iodo-1H-pyrazolo[3,4-b]pyridine is used as a raw material, which is cheap and easily available. In the first step, it may react with o-fluorobenzyl bromide
at room temperature in the presence of potassium carbonate (K.sub.2CO.sub.3) to obtain compound (10), with a yield of 71.16%; in the second step, the reaction with zinc cyanide and others obtains compound (6), with a yield of 63.7%; in the third step,
the reaction with sodium methoxide, ammonium chloride, acetic acid and methanol obtains compound (8); in the fourth step, the reaction with hydrogen chloride gas obtains 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride. The
total yield of the last two steps is 99%. This method features cheap and easily available raw materials, high yield and moderate reaction conditions. It is a synthesis method with a value of large-scale preparation.

DETAILED DESCRIPTION OF THE
EMBODIMENTS

Example 1

Synthesis of Compound (10)

##STR00007##

Add 400 g (1.63 mol, 1.0 eq) of 3-iodo-1H-pyrazolo[3,4-b]pyridine, 369 g (1.96 mol, 1.2 eq) of o-fluorobenzyl bromide and 450 g (3.27 mol, 1.5 eq) of K.sub.2CO.sub.3 dissolved in 4 L of DMF into a 5 L 4-neck flask and react for 10 h at room
temperature. Pour the reaction solution into water after thorough reaction as monitored by TLC, stir it to appear a plenty of grey solid, filter and recrystallize PE: EA=5:1 to obtain 411 g of light yellow solid. The yield is 71.16%.

Add 919.7 g (3.646 mol, 1.0 eq) of compound (6) and 7 L of MeOH into a 10 L 4-neck flask, add 295 g (5.469 mol, 1.5 eq) of MeONa under stirring, stir 2 h at room temperature, add 329 g (5.469 mol, 1.5 eq) of CH.sub.3CO.sub.2H and 293 g (5.469
mol, 1.5 eq) of NH.sub.4Cl after that TLC indicates the raw material has disappeared and been completely converted into intermediate (7), adopt heating reflux and take reaction overnight, lower the temperature after thorough reaction as monitored by TLC
to appear a plenty of solid, filter and wash with DCM to obtain 981 g of white solid, which is compound (8), and directly used in next step.

Synthesis of Compound (11)

##STR00010##

Add 981.0 g (3.646 mol, 1.0 eq) of compound (8) into 5 L of MTBE, stir to form a suspension, input HCl gas for about 2.5 h, filter, wash with DCM and dry to obtain 1103.7 g of white solid. The total yield in the two steps is 99.0%. The purity
is 99%.